US5776985A - Fluorinated propranolol and related methods - Google Patents

Fluorinated propranolol and related methods Download PDF

Info

Publication number
US5776985A
US5776985A US08/748,894 US74889496A US5776985A US 5776985 A US5776985 A US 5776985A US 74889496 A US74889496 A US 74889496A US 5776985 A US5776985 A US 5776985A
Authority
US
United States
Prior art keywords
propranolol
compound
fluorinated
beta
antioxidant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/748,894
Other languages
English (en)
Inventor
William B. Weglicki
I. T. Mak
Hassan Y. Aboul-Enein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
George Washington University
George Washington University Hospital
Original Assignee
George Washington University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by George Washington University filed Critical George Washington University
Priority to US08/748,894 priority Critical patent/US5776985A/en
Assigned to GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER reassignment GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MAK, I. T.
Assigned to GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER reassignment GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABOUL-ENEIN, HASSAN Y.
Assigned to GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER reassignment GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WEGLICKI, WILLIAM B.
Application granted granted Critical
Publication of US5776985A publication Critical patent/US5776985A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids

Definitions

  • the field of this invention is pharmaceuticals which act as beta blockers and pharmaceuticals that act as antioxidants. Specifically, this invention relates to beta blockers with amplified and controlled antioxidant properties.
  • Beta blockers such as various forms of propranolol are known. It is known that a variety of heart and hypertension problems can be treated with beta blockers. However, an excessive treatment of beta blockers can cause undesirable side effects in patients.
  • Antioxidant agents are also known. It is also known that treatment by antioxidants may be used to treat similar and related heart and hypertension problems.
  • the inventors discovered significant membrane antioxidant activity for some fluorinated propranolol analogs.
  • the antioxidant potency of these preparations increases with the degree of fluorination.
  • Experimental results indicate that different isomers of propranolol (some of which may be pharmacologically active as beta blockers and some of which may be pharmacologically inactive as beta blockers) display equipotent antioxidant activity. That is, their antioxidant activity is independent of their pharmacological beta blocker activity.
  • Free radicals in the cell membranes cause lipid peroxidative damage and protein oxidative damage. Antioxidants neutralize the free radicals before they can cause this damage or may block the early "chain reaction" of peroxidation in the cell membranes.
  • Fluorination of propranolol increases the lipophilicity of the propranolol analogs and thereby causes the higher partitioning of the antioxidant agents into the biomembranes of cells; therefore, these fluorinated propranolol beta blockers have greater antioxidant effect than the unfluorinated propranolols, because the fluorinated agents enter the membrane in greater quantity than the unfluorinated propranolols.
  • the present invention includes fluorinated propranolol analogs and methods of use as simultaneous beta blockers and amplified antioxidants for the treatment of heart failure, hypertension, and related diseases.
  • the present invention further includes mixtures of (1) fluorinated antioxidant non-beta blocking isomers of propranolol, with (2) fluorinated antioxidant beta blocking isomers of propranolol, in a range of ratios.
  • This range of mixtures offers a range of choice of beta blocking intensity to correspond to a selected level of antioxidant activity, thereby avoiding excessive beta blocking for an individual case for a desired antioxidant impact. That is, for a given antioxidant impact, the simultaneous beta blocker impact can be controlled.
  • fluorinated antioxidant beta blocking propranolols may include excessive beta blockade at higher dosage.
  • the mixtures of the present invention offer choices that avoid the problems associated with excessive beta blocking, while achieving the targeted antioxidant benefit.
  • This fluorination method may be applied to other beta blocking agents such as aterolol, metoprolol, and similar drugs, to enhance their lipophilicity and positioning into biological membranes.
  • FIG. 1 shows the chemical structure of: propranolol (1a), trifluoroethyl-propranolol (1b), pentafluoropropyl-propranolol (1c), heptafluorobutyl-propranolol (1d).
  • the schematic illustrates the common structure together with the numbers of the atoms.
  • the table below the schematic gives the side chains R1 and R2 in the four molecules.
  • FIG. 2 shows propranolol viewed perpendicular to its a) longitudinal (primary or 1°) axis, b) secondary (2°) axis, and c) tertiary (3°) axis.
  • FIG. 3 shows the atomic charges and the structure of a) propranolol, b) trifluoroethyl-propranolol, c) pentafluoropropyl-propranolol, and d) heptafluorobutyl-propranolol.
  • FIG. 4 shows the distribution of charge densities in a) propranolol, b) trifluoroethyl-propranolol, c) pentafluoropropyl-propranolol, and d) heptafluorobutyl-propranolol. For each molecule two views are presented, one perpendicular to the 2° axis and the other perpendicular to the 3° axis.
  • FIG. 5 shows the distribution of electrostatic potential in a) propranolol, b) trifluoroethyl-propranolol, c) pentafluoropropyl-propranolol, and d) heptafluorobutyl-propranolol. This view is perpendicular to the 3° axis of each molecule. The changes in the dotted contours represent the negative values.
  • FIG. 6 shows the antioxidant activities of fluorinated propranolol analogs.
  • FIG. 7 shows the antioxidant activities of nonfluorinated propranolol analogs.
  • FIG. 8 shows the protective effects of F2 and F2-R on R.(DHF+Fe)-induced loss of endothelial cell glutathione (GSH).
  • FIG. 9 shows the molecular structure of D-propranolol, and L-propranolol, which are both prior art.
  • Table 1 shows optimized energies of the molecules.
  • Table 2 shows coordinates of propranolol (1a).
  • Table 3 shows coordinates of trifluoroethyl-propranolol (1b).
  • Table 4 shows coordinates of pentafluoropropyl-propranolol (1c).
  • Table 5 shows coordinates of heptafluorobutyl-propranolol (1d).
  • Table 6 shows fluorinated propranolol analogs which are part of the present invention.
  • Table S1 shows important bond angles (°) for the fluorinated analogs.
  • Table S2 shows important torsion angles (°) for the fluorinated analogs.
  • Table S3 shows dipole moments of the molecules.
  • FIG. 9 shows the molecular structure of D-propranolol (i.e., right or R-propranolol) and L-propranolol (i.e., left or S-propranolol), which are both prior art.
  • L-propranolol is a beta blocker, that is, it is pharmacologically active.
  • D- (or right-) propranolol is not a beta-blocker.
  • Table 6 shows the molecular structure of the fluorinated propranolol analogs, which are part of the present invention.
  • the inventors have found that D- and L-propranolol have about the same anti-oxidant potency.
  • the fluorination of propranolol enhance their antioxidant potency and protect cardiovascular, neurological and other tissues from free radical-mediated injury.
  • Clinical problems such as heart failure, myocardial infarction, ischemia/reperfusion injury, stroke, and related diseases), where excess free radicals contribute to mechanisms of injury, benefit from treatment by fluorinated beta blockers, including treatment by a combination of fluorinated D-propranolol and fluorinated L-propranolol.
  • Chemical modifications include variable degrees of fluorination of these molecules to provide variable clinical efficacy.
  • the new combination of a fluorinated active beta blocker e.g., L-propranolol, at 5-10% of a full dose
  • a fluorinated inactive beta blocker e.g., D-propranolol at 95-90% of a full dose
  • Both oral and other methods of administration can be used.
  • the therapeutic strategies include delivery of fluorinated antioxidant doses combined with effective beta blocking doses to maintain the patient on adequate beta blockade, while enhancing greatly the antioxidant therapy.
  • the non-beta blocking form e.g., fluorinated D-propranolol
  • the fluorinated drug may be administered alone or as an adjunct to other therapies, to treat diseases including thrombolysis, organ preservation, heart failure, restenosis of angioplasty arteries, inflammatory processes (e.g. in skin, lungs, and eyes) and other conditions.
  • Propranolol chemically known as 1-isopropylamino-3-)1-naphthyloxy)-2-propanol (see FIG. 1a) is the model parent drug for non-selective ⁇ -blockers, a "pure" antagonist of catecholamines at the receptor sites.
  • propranolol The principal toxicities of propranolol result from the blockade of cardiac, vascular, or bronchial ⁇ -adrenoceptors. Most important predictable untoward reactions are in patients with reduced myocardial reserve, asthma, peripheral vascular insufficiency, and diabetes. Some patients experience a beta blocker withdrawal syndrome when discontinued after a long use. The manifestations of this are anxiety, tachycardia, increased intensity of angina, heart attack, or increase in blood pressure. These side effects of propranolol are not desired.
  • the four structures above were created by the inventors using HyperChem for Windows and optimized with a semi-empirical technique, namely AM1.
  • the Polak-Ribiere conjugate gradient method was used for optimization.
  • the minimum energy states (with minimum binding energy) that were achieved were as shown in Table 1.
  • the naphthyl moiety in all the compounds is flat.
  • the bond angles of the naphthyl group are all approximately 120° each with minimal torsion within the rings. All the other bond angles range between 105° and 125°.
  • the side chain zigzags around an axis in the plane of the naphthyl group (view a in FIG. 2). If the molecule is turned to view it from a side so that the naphthyl moiety becomes a straight line (view b in FIG. 2), the side chain is also more or less a straight line with its axis making an angle of approximately 173.5° with the plane of the naphthyl group.
  • the bond with 017 atom makes an angle of about -63° and the bond of the C34 atom an angle of about 121° with the plane of the rings.
  • the side chain zigzags in a similar way as in view a (FIG. 2) of the parent and its axis makes an angle of approximately 178.5° with the plane of the rings (in a view similar to view b of FIG. 2). While, when the side chain projects perpendicularly into the paper plane (like view c in FIG. 2) the bond with 017 atom makes about 66°, the C36 atom an angle of about 45.5° and the bond with C37 atom an angle of about -63.5° with the plane of the rings.
  • zigzagging of the non-fluorinated portion of the side chain is similar to the parent (like view a in FIG. 2) and its axis makes an angle of approximately 177.5° with the plane of the rings (like in view b of FIG. 2).
  • the --CF 3 group projects almost perpendicularly to the rest of the side chain (i.e., the non-fluorinated portion) in the direction opposite to that of the 017 atom.
  • the bond with the 017 atom makes an angle of almost -118°, the bond of the C35 atom of almost -132°, and the bond of C37 atom of almost 115° with the plane of the rings.
  • the zigzagging of the non-fluorinated portion is similar to the parent (like in view a of FIG. 2) and the axis of the non-fluorinated portion of the side chain makes an angle of about 178.5° with the plane of the rings (like in view b of FIG. 2), the first portion of the fluorinated region of the side chain (i.e., C33-C37 link) is at about 93° to the non-fluorinated region of the side chain and the second region (i.e., C37-C39 link) is at about 254.5° to the first link (both of these in view b).
  • the bond of the 017 atom makes an angle of about 67° with the plane of the rings, the bond of C35 atom an angle of about 52°, and the bond of C37 atom of about -60°.
  • the sizes of the 4 molecules are not very different. In fact, there is a reduction in size from the parent to the 1st derivative (-CF 3 ).
  • the dimensions of the molecule boxes together with the molecular volumes for the four molecules are as follows: propranolol 335.162 ⁇ 3 , trifluoroethyl propranolol 280.183 ⁇ 3 , pentafluoropropyl-propranolol 382.636 ⁇ 3 , and heptafluorobutyl propranolol 395.135 ⁇ 3 .
  • the heat of formation of the "CF 2 " increment group may be estimated and turns out to be in the range of -97.3 kcal/mol to -109.7 kcal/mol, with a mean of -103.5 kcal/mol.
  • Heat of formation attributable to CF 3 may be estimated to be approximately -160 kcal/mol.
  • the estimated heats of formation for the three derivatives from these figures come out to be -218 kcal/mol, -321 kcal/mol and -424 kcal/mol which are not significantly different from the respective values obtained from the AM1 calculations (given in Table 1 below).
  • the molecules do exhibit a sudden increase in the dipole moment from 1.303 Debyes to 4.142 Debyes when the two terminal methyl groups are replaced one by a hydrogen and the other by a -CF 3 group in 1b.
  • fluorines there is a further increase in the dipole moment (to 4.162 and then to 4.497 Debyes), but not as dramatic. This simple measure indicates a significant redistribution of charge density. To quantify this change further, charge distributions and electrostatic potentials were studied and are discussed below.
  • the changes in the charges distribution in the four compounds involve the ether oxygen (011) and all the terminal fluorines.
  • propranolol most of the charge is concentrated on the ether oxygen.
  • the charge is most distributed around the same oxygen and the terminal fluorines and to a lesser extent around the nitrogen.
  • charge distribution is again mostly around the ether oxygen (011) and the terminal fluorines and to a lesser extent around the hydroxyl oxygen (017) and the nitrogen.
  • the charge density distribution in the different molecules is shown in FIG. 4.
  • the sites of most negative electrostatic potential move towards the terminal of the molecules from the parent to the derivatives as the number of fluorines increase.
  • the site is near the ether oxygen, in 1b it is more or less equally distributed between the ether oxygen and the fluorinated terminal, in 1c the region of influence of the electrostatic potential progressively increases as it does again in 1d.
  • the volume of this influence covers the region occupied by the nitrogen and the terminal fluorines in the three derivatives, but the increase in the number of fluorines make this region bigger.
  • the most likely site of protonation or electrophilic attack move from the ether oxygen in the parent through equally likely at this oxygen and the terminal to more likely at the fluorinated portion of the side chain terminal particularly in 1d.
  • the regions are similar to those suggested by the charge density. As the number of fluorines increase in the molecule the corresponding region of influence also increases and reactivity would be expected to be stronger (i.e., stronger bonds are more likely to form). It is possible the binding to the receptor involves both the ether oxygen and the fluorines.
  • liver microsomal membranes (0.2 mg/ml) were resuspended in PBS.
  • the membrane samples were pretreated for 20 minutes with or without the drugs, before adding the free radical components (R.), which consisted of DHF (0.83 mM) and Fe (25 ⁇ M FeCl 3 ) chelated by ADP (250 ⁇ M).
  • R. free radical components
  • membrane peroxidation was measured by the TBA (thio-barbituric acid) method as described in Mak & Weglicki, Methods in Enzymology 234: 620-630, 1994.
  • Drug effects are represented by the percentage of inhibition of the oxidation product formation.
  • Liver microsomal membranes were isolated from homogenized liver tissue by differential centrifugation according to the procedure of Mak & Weglicki, Pharmacological Research 25: 25-30, 1992.
  • the oxygen free radical system generates oxygen radicals to oxidize rat liver membranes in the experiment whose results are shown in FIGS. 6 and 7, and to oxidize endothelial cell glutathione in the experiment whose results are shown in FIG. 8.
  • oxygen radicals are generated by the addition of DHF, Fe, and ADP.
  • oxygen radicals are generated by the addition of DHF and Fe. The detailed procedure and methods were described in Mak & Weglicki Methods in Enzymology. 234: 620-630, 1994).
  • the items F-4, F-3, and F-2 are the preparations shown as 1b, 1c, and 1d, respectively, in FIG. 1, and are part of the present invention.
  • H-4, H-3, and H-2 are the un-fluorinated forms of F-4, F-3, and F-2, respectively.
  • FIGS. 6 and 7 show that fluorination significantly increases the antioxidant activity of the propranolol analogs.
  • the EC 50 concentration of test compound which will inhibit membrane lipid peroxidation by 50%
  • the fluorinated compounds are much more effective antioxidants.
  • Table 6 shows the molecular structure of types of fluorinated propranolols, that are part of the present invention.
  • the parent compound, a variation of propranolol is shown at the top of the Table.
  • the -R structures of F-4, F-3, and F-2 (1b, 1c, and 1d, respectively), are shown, with other data.
  • Equivalent data for H-4, H-3, and H-2 (which are the unfluorinated forms of F-4, F-3, and F-2) are also shown.
  • the S (or left) enantiomer of F-2 is shown, as is the R- (right or D-) enantiomer of F-2.
  • the anti-oxidant potency for each analog of propranolol is about the same for both the left and right form of that analog.
  • racemic propranolol 50 percent D-propranolol and 50 percent C-propranolol was used for the control (un-fluorinated) propranolol.
  • the left-most column shows the GSH level of the endothelial cells ("Veh.") without radicals or propranolol treatment.
  • the second column shows a 50 percent loss of the GSH caused by treatment with the radical system only.
  • the third column (“+Prop.") shows treatment of the cells (with radicals R.) with racemic propranolol (50 percent D-propronolol and 50 percent L-propranolol) only.
  • the fourth column (“+F2”) shows the effect of treating the cells (with radicals R.) with a racemic mixture of 50 percent Left-F-2, and 50 percent Right F-2.
  • the fifth column shows the effect of treating the cells (with radicals R.) with Right F-2.
  • the drugs Propranolol, the 50/50 mixture, and F2R, respectively
  • the fluorinated forms of propranolol of the present invention can be used to treat any disease that is responsive to anti-oxidant treatment.
  • the right (or D-) forms of the fluorinated propranolols would be especially indicated for treatment where beta-blocker effects or toxicity are anticipated as a problem.
  • Active beta blockers bind to the beta adrenergic receptors with high affinity whereas inactive compositions (non-beta blockers) will not.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US08/748,894 1995-11-16 1996-11-14 Fluorinated propranolol and related methods Expired - Fee Related US5776985A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/748,894 US5776985A (en) 1995-11-16 1996-11-14 Fluorinated propranolol and related methods

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US683595P 1995-11-16 1995-11-16
US879095P 1995-12-18 1995-12-18
US08/748,894 US5776985A (en) 1995-11-16 1996-11-14 Fluorinated propranolol and related methods

Publications (1)

Publication Number Publication Date
US5776985A true US5776985A (en) 1998-07-07

Family

ID=26676127

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/748,894 Expired - Fee Related US5776985A (en) 1995-11-16 1996-11-14 Fluorinated propranolol and related methods

Country Status (9)

Country Link
US (1) US5776985A (de)
EP (1) EP0883596B1 (de)
JP (1) JP2000500451A (de)
AT (1) ATE205470T1 (de)
DE (1) DE69615221T2 (de)
DK (1) DK0883596T3 (de)
ES (1) ES2163661T3 (de)
PT (1) PT883596E (de)
WO (1) WO1997018184A1 (de)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337628A (en) * 1962-11-23 1967-08-22 Ici Ltd 3-naphthyloxy-2-hydroxypropylamines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337628A (en) * 1962-11-23 1967-08-22 Ici Ltd 3-naphthyloxy-2-hydroxypropylamines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Farooqi et al., Chemical Abstracts, vol. 124, abstract 175051y, 1996. *

Also Published As

Publication number Publication date
EP0883596B1 (de) 2001-09-12
DE69615221T2 (de) 2002-06-13
DK0883596T3 (da) 2002-01-21
EP0883596A4 (de) 1999-05-06
EP0883596A1 (de) 1998-12-16
WO1997018184A1 (en) 1997-05-22
JP2000500451A (ja) 2000-01-18
PT883596E (pt) 2002-02-28
DE69615221D1 (de) 2001-10-18
ATE205470T1 (de) 2001-09-15
ES2163661T3 (es) 2002-02-01

Similar Documents

Publication Publication Date Title
FI77018B (fi) Analogifoerfarande foer framstaellning av antidepressivt aktiv (-)-enantiomer av n-metyl-n-/3-(2-metylfenoxi) -3-fenylpropyl/amin och dess farmaceutiskt godtagbara salt.
PT88251B (pt) Processo para a preparacao de novos derivados de ariloxi-indenamina com actividade antidepressiva e de composicoes farmaceuticas que os contem
JPH0211579B2 (de)
JPH07119193B2 (ja) 心血管系医薬としてのアルカノールアミン誘導体
EP0322389B1 (de) Antiarrythmische Derivate 2
WO1983000688A1 (en) 2-ad2'-hydroxy-3'-(1,1-dimethylpropylamino)-propoxybd-beta-phenylpropiophenone, preparation and pharmaceutical compositions
US5776985A (en) Fluorinated propranolol and related methods
NZ195702A (en) 7-(3-(isopropyl or t-butyl)amino-2-hydroxypropoxy)-indolin-2,3-diones
WO1997018184A9 (en) Fluorinated propranolol and related methods
US5242943A (en) 3-aminopropoxyphenyl derivatives, their preparation and pharmaceutical compositions containing them
US4562206A (en) Orally effective inotropic compounds
EP0116825A1 (de) Aryloxypropanolaminderivate, Verfahren zu deren Herstellung, pharmazeutische Präparate und therapeutische Anwendung
US5410080A (en) Non-metabolizable clomiphene analogs for treatment of tamoxifen-resistant tumors
EP0151052B1 (de) Aminoäthylimidazole, pharmazeutische Zusammensetzungen die sie enthalten und Verfahren zu ihrer Herstellung
JP4241926B2 (ja) ３―アミノ―プロポキシフェニル誘導体（１）
US5051445A (en) 3-amino-propyloxyphenyl derivatives, their preparation and pharmaceutical compositions containing them
EP0003461B1 (de) Aminoalkoholderivate von ortho-Hydroxymethylcinnamat, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
EP0106816A2 (de) 3,4-Dihydro-2H-1,4-Benzothiazin-3-one-Alkanolaminooxy-Derivate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
IE51447B1 (en) Alkoxy-acyl carnitines,process for their preparation and pharmaceutical compositions containing same
JPH0116829B2 (de)
US3828076A (en) 3-(3-substituted amino-2-hydroxypropoxy)-2-substituted-4-pyranones
GB2044251A (en) Phenoxypropanolamine derivatives
JPH0318607B2 (de)
JPH09268162A (ja) イソプレン誘導体
EP0020266A1 (de) Cyan-2-hydroxy-3-benzofuran- und Benzo(b)thiophenderivate, ihre Herstellung und ihre Verwendung in der Heilkunde

Legal Events

Date Code Title Description
AS Assignment

Owner name: GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER, DISTR

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:WEGLICKI, WILLIAM B.;REEL/FRAME:008388/0120

Effective date: 19961203

Owner name: GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER, DISTR

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ABOUL-ENEIN, HASSAN Y.;REEL/FRAME:008388/0125

Effective date: 19950724

Owner name: GEORGE WASHINGTON UNIVERSITY MEDICAL CENTER, DISTR

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MAK, I. T.;REEL/FRAME:008388/0131

Effective date: 19961203

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20020707